7. Project Summary/Abstract The development of both tolerance and autoimmunity is dependent on the presentation of self-antigens in the thymus and periphery. Thymic tolerance requires recognition of self-antigens leading to negative selection, i.e. deletion of self-reactive T cell clones; or selection into Foxp3+ regulatory T (Treg) cells, important for maintaining immune homeostasis in the periphery. In the periphery, presentation of self-antigens results in maintenance and induction of regulatory T cells to promote tolerance, but can also facilitate autoimmunity via induction of self-reactive effector cells. These processes are driven by antigen presenting cells (APCs), of which there are several subsets. Previously, we showed that Batf3-dependent CD8?+ DCs play an important role in thymic tolerance as the major recipient of antigen transfer from medullary thymic epithelial cells (mTECs), which produce a variety of self-antigens via the effect of the transcription factor Aire. Here, we propose to continue our studies on the role of CD8?+ DCs in tolerance and autoimmunity. We will continue our ongoing studies of thymic CD8?+ DCs with the goal of understanding the mechanisms of antigen transfer (Aim 1). We will also ask whether CD8?+ DCs present a unique array of self-antigens in the periphery with the goal of identifying the origin of some of these antigens (Aim 2). Finally, we will determine whether peripheral CD8?+ DCs are involved in effector vs regulatory T cell differentiation in response to self-antigens (Aim 3). If successful, this grant will offer new insights regarding the role of CD8?+ DCs in providing antigen-specific and T cell developmental niches in the thymus and periphery that may control the balance between tolerance and autoimmunity.